CAR T Cells: 'Validation That They Keep Living and Keep Working'

Zosia Chustecka

December 02, 2018

SAN DIEGO — New longer-term data with chimeric antigen receptor (CAR) T-cell therapies are showing durable responses, with many patients sustaining deep responses that are now lasting for several years.

Long-term data with tisagenlecleucel (Kymriah, Novartis) were presented here at American Society of Hematology (ASH) 2018 meeting and highlighted at an ASH press briefing.

"What we are seeing is a validation that these therapies aren't just something that are a temporizing measure…based upon the duration of the effectiveness of these therapies, there are patients for whom you really can look at the prospect of a cure," commented Joseph Alvarnas, MD, from the City of Hope in Duarte, California, who moderated the briefing.

Dr Joseph Alvarnas

As the data go farther out, now approaching 3 years, "we are becoming more excited that this technology in fact changes the nature of the disease for some patients," he told Medscape Medical News.

"With other therapies, we have seen responses, but in time the responses diminish and the patients may submit to a relapse, but what you see now are that these CAR T cells persist in the body," he explained.

Patients who respond develop B-cell aplasia as a side effect, and this is validation that these products persist in the body, he commented. "This is a living drug, and this is validation that it keeps living and keeps working."

Not for everyone, however. "There is a subset of patients for whom these products stop working, and the big questions are now how to identify them, and what to do next with these patients," Alvarnas said.

Hints at answers to both questions were also presented here at the ASH meeting.

A new way of measuring responses, which involves immunoglobulin next-generation sequencing (NGS) to assess minimal residual disease (MRD; abstract 1551), is far more sensitive than previous tests. It offers a way of identifying patients with the best responses who are likely to need no further therapy and patients for whom another intervention would be beneficial.  

What to do next for these patients is still unclear. There is a heated debate over whether they would benefit from going on to receive a hematopoietic stem cell transplant (HSCT), and that seems to depend on whether they have already had one (abstract 967). Another option being explored is the addition of other therapies: A small study suggests that when responses start waning, using checkpoint inhibitors, such as pembrolizumab and nivolumab, to take the brake off the immune system appears to improve responses (abstract 556).

Longer-term Data in Leukemia

The longest follow-up with CAR T-cell therapy is in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). The first patient, Emily Whitehead, is still alive and well more than 8 years after receiving one infusion.

Dr Stephan Grupp

The doctor who treated her, and many patients since, is Stephan Grupp, MD, PhD, from the Children's Hospital of Philadelphia, Pennsylvania. At the ASH meeting, he presented 24-month follow-up analysis of the pivotal  ELIANA study (abstract 895).

"This was the first global trial of a CAR T cell with a global supply chain," he said.

"This 2-year analysis is an exciting milestone for the field, as it is the longest follow-up data for a multicenter CAR T-cell trial for those patients who have failed to respond to other treatment options," he added.

Among 79 evaluable patients, who were followed for at least 3 months or discontinued earlier, 82% achieved complete response (CR) or CR with incomplete blood count recovery within 3 months of infusion; among these responding patients, 98% had negative MRD.

The relapse-free survival rate was 62% at 24 months, and the median duration of remission (mDOR) and median overall survival (OS) have not yet been reached.  The probability of OS was 76% at 12 months and 66% at 24 months.

These data show that many patients have deep and sustained responses, he said. "Seeing that the majority of responding patients from ELIANA are still in remission for this long after a one-time infusion further establishes Kymriah as a truly transformative treatment option," he commented in a statement.

Grupp suggested that for some patients, the one-time infusion of CAR T cells is sufficient. He noted that patients who were identified by NGS as having no MRD in bone marrow at day 28 had superior outcomes, and they are a group possibly suited for no further therapy (such as a transplant).

The updated analysis shows no new safety signals, and the side effect profile was consistent with what has been reported previously. Grade 3/4 cytokine release syndrome (CRS) — as defined by the rigorous Penn Grading Scale — occurred in 49% of patients. Within 8 weeks of infusion, 13% of patients experienced grade 3 neurologic events, with no grade 4 events, and no cerebral edema.

Longer-term Data in Lymphoma

The other approved indication for CAR T cells is the treatment of adults with relapsed/refractory (r/r) diffuse B-cell lymphoma (DBCL).

Longer-term data with tisagenlecleucel come from the pivotal JULIET trial, presented at the meeting (abstract 1684) by Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute, in Portland,  and simultaneously published online  in  the New England Journal of Medicine.

Dr Richard Thomas Maziarz

This was a 19-month analysis of 99 patients who were followed for at least 3 months or discontinued earlier.

The overall response rate after a median of 19 months of follow-up was 54% (with a CR of 40% and partial response of 13%).

"We are seeing a change in the natural history of the disease, " Maziarz commented at the press briefing. Historically in such patients with r/r disease, who have had multiple lines of chemotherapy and transplants, a CR would be rare, with a CR rate less than 10%, he said.

Of note, 54% of patients who initially had a partial response ended up having a CR, which suggests that the cell product persists viably and remains active in vivo over time, Maziarz commented.

The mDOR was not reached at the time of analysis, indicating that most responders were still experiencing a response at the time of analysis. The relapse-free probability was 66% at 6 months and remained consistent at 64% between the 12-month and 18-month analyses.

The median OS for all infused patients was 11.1 months and was not reached for patients in CR. The OS probability was 48% at 12 months and 43% at 18 months (maximum follow-up, 29 months).

"We're seeing that the responses are sustained," Maziarz commented. "There are a significant number of patients who are staying free of disease."

The safety profile observed in the 19-month follow-up is consistent with what has been reported previously, and no treatment-related deaths occurred. Grade 3/4 CRS, as defined by the Penn Grading Scale, was reported in 23% of patients and was treated with tocilizumab (in 16%) and steroids (in 11%).  Grade 3/4 neurologic adverse events were seen in 11% of patients and were managed with supportive care.

"CAR T therapy represents a potentially life-saving alternative for these patients, who now have a therapy that can help them achieve durable remissions even after other therapies, including transplant, have failed," commented Stephen J. Schuster, MD, director of the Lymphoma Program at the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, and lead author on the paper.

Another CAR T Cell for Lymphoma

Longer-term data on patients with r/r DBCL were also presented at the meeting for the other CAR T-cell product approved for this indication, axicabtagene ciloleucel (axi-cel; Yescarta, Kite/Gilead).

These 2-year follow-up data from the ZuMA-1 trial were presented at the meeting (abstract 2967) by Sattva Neelapu, MD, professor of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and simultaneously published online in The Lancet Oncology.

"This two-year assessment demonstrates that axi-cel can induce durable remissions in a substantial proportion of patients with an acceptable long-term safety profile," said Neelapu in a statement. "There also is evidence of gradual B-cell recovery in most patients with refractory large B-cell lymphoma who otherwise have limited treatment options."

The new analysis, with a median follow-up of 27.1 months for 101 patients, showed that 83% of patients achieved an objective response; 58% had a CR, and 39% report ongoing responses.

Median OS was not reached, and the median progression-free survival was 5.9 months, the team reported.

About half of the patients who were evaluable (52 [48%] of 108 patients) had grade 3 or worse serious adverse events. This included CRS in 12 (11%) patients and neurologic events in 35 (32%) patients, the team reported.

Asked to comment on how these data with Yescarta compare to those with Kymriah in patients with r/r DBCL, Maziarz said that the efficacy results are broadly similar but that the side effects and cost of the two products differ.  

Cost and Reimbursement Remain an Issue

The huge cost of the CAR T cells, plus the cost of the medical care involved in treating patients with this new technology, has raised some big issues for reimbursement, as previously reported by Medscape Medical News.  

However, Grupp said at the press briefing that in the specific patient population he treats, pediatric and young adults (<21 years) with r/r ALL, "our ability to treat these patients has not been compromised by insurance issues at this time."

Grupp has treated 30 such patients with Kymriah since it was approved by the US Food and Drug Administration in August 2017. He said that he has not encountered any problems with commercial insurers paying for the treatment. Some patients have also received this therapy on  Medicaid, and "while this differs from state to state, and so you are reinventing the wheel every time, the reality is that we are getting those patients paid for as well," he said.

"So from the point of view of reimbursement of the cost of the product, that is going okay, and for the reimbursement of the hospital costs, in most cases this does not seem to be a problem," Grupp said, but he emphasized that this was "very pediatric specific."

It's quite a different story for adults with r/r DBCL, commented Maziarz. Many of these older patients are on Medicare, and there have been some huge problems with getting reimbursement through this system, specifically to cover the cost of hospital care when these new products are administered in the inpatient setting. "These treatments are moving faster than our healthcare systems can manage," he said. There are plans to move this therapy to an outpatient setting, but then problems would arise if complications develop and the patient must be transferred to inpatient care, he explained.

At present, these issues with reimbursement mean that some hospitals are being hit with a loss per patient, and this is not sustainable, added Alvarnas. He has been involved with talks between ASH and the Centers for Medicare & Medicaid Services (CMS), and they are making some progress "to create a new language for reimbursement," he said.

The costs involved with CAR T-cell therapy, for example with CRS or neurologic side effects, have never been seen before, and so new billing pathways must be created, he added.

In fact, data released earlier this year suggested that the cost of treating patients with r/r DBCL in the third- and fourth-line setting probably exceeds that of using a CAR T cell for these patients, he noted. But CMS billing needs to catch up to reflect this, he added.

Other countries are also struggling with reimbursement issues for CAR T cells.

For example, in the United Kingdom, the National Institute for Clinical Excellence (NICE) recently approved as cost-effective the use of Kymriah for pediatric patients with r/r ALL, which means that this product is  available on the National Health service in England and Wales.

However, NICE rejected as not cost-effective the use of Kymriah when used to treat adults with r/r DBCL, but decided that the other CAR T cell, Yescarta, was cost-effective for this indication.

The ELIANA and JULIET trials were funded by Novartis. The ZUMA-1 trial was funded by Kite/Gilead. Alvarnas reports consultancy and honoraria from the American Journal of Managed Care, honoraria from the National Comprehensive Cancer Networks, and being on the speaker's bureau for Novartis.  Grupp reports consultancy for Novartis, Jazz Pharmaceuticals, and Adaptimmune and reports University of Pennsylvania patents and royalties. Maziarz reports consultancy for and honoraria from Novartis, Incyte, Juno Therapeutics, and Kite Therapeutics, and patents and royalties from Athersys Inc.  Neelapu reports consultancy for Celgene; research funding from Cellectis, Poseida, Merck, Karus, Bristol-Myers Squibb, Novartis; consultancy and research funding from Acerta; and serving on the advisory committee for Unum Therapeutics and Kite/Gilead.

American Society of Hematology (ASH) 2018. ELIANA update, abstract 895, to be presented December 3; JULIET update, abstract 1684, presented December 1; ZUMA-1 update abstract 2968, presented December 2.

JULIET: N Engl J Med. Published online  December 1, 2018. Abstract

ZUMA-1: Lancet Oncol. Published online December 2, 2018. Abstract

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